Drug resistance and multidrug resistance modulators

ABSTRACT

Drug and multidrug resistant modulators of the formula:                    
     where R 1  and R 2  are independently hydrogen or halo; A is —CH 2 —CH 2 —, —CH 2 —CHR 4 —CH 2 —, or —CH 2 —CHR 5 —CHR 6 —CH 2 —, where R 4  is —H, —OH, or acyloxy; one of R 5  or R 6  is —H, —OH, or acyloxy, and the other is —H; R 3  is a polyaryl; and pharmaceutically acceptable salts and solvates thereof, are described and claimed. Use of the new compounds in the preparation of pharmaceutical compositions is described and claimed. In addition, methods for treating drug and multidrug resistance in various diseases using a compound, or pharmaceutically acceptable salt or solvate thereof, of this invention are described and claimed. Also, methods of enhancing oral bioavailability of a drug and methods of enhancing bioavailability of a drug to the brain using a compound, or pharmaceutically acceptable salt or solvate thereof, of this invention are described and claimed.

FIELD OF THE INVENTION

This is a divisional application of pending prior application Ser. No.08,873,782, filed on Jun. 12, 1997, of Julian Stanley Kroin and BryanHurst Norman, titled Drug Resistance and Multidrug ResistanceModulators, now U.S. Pat. No. 6,025,359, which claims priority to U.S.provisional application Ser. No. 60/020,807, filed Jun. 17, 1996, ofJulian Stanley Kroin and Bryan Hurst Norman, titled Drug Resistance andMultidrug Resistance Modulators.

This invention relates to the field of synthetic organic chemistry.Specifically, the invention relates to pharmaceutical compounds that areuseful in the field of drug resistance and multidrug resistance.

BACKGROUND OF THE INVENTION

Among the problems faced in certain types of drug therapy, includingcancer chemotherapy and malaria drug regimens. The resistance means, forexample, that cancerous tumors that have responded well initially to aparticular drug or drugs, later develop a tolerance to the drug(s) andcease responding. Drug resistance is the name given to the circumstancewhen a disease (e.g., malaria or cancer, does not respond to a treatmentdrug or drugs. Drug resistance can be either intrinsic, which means thedisease has never been responsive to the drug or drugs, or it can beacquired, which means the disease ceases responding to a drug or drugsthat the disease had previously been responsive to. Multidrug resistanceis a specific type of drug resistance that is characterized bycross-resistance of a disease to more than one functionally and/orstructurally unrelated drugs. Multidrug resistance in the field ofcancer, is discussed in greater detail in “Detoxification Mechanisms andTumor Cell Resistance to Anticancer Drugs,” by Kuzmich and Tew,particularly section VII “The Multidrug-Resistant Phenotype (MDR),”Medical Research Reviews, Vol. 11, No. 2, 185-217, (Section VII is atpp. 208-213) (1991); and in “Multidrug Resistance andChemosensitization: Therapeutic Implications for Cancer Chemotherapy,”by Georges, Sharom and Ling, Advances in Pharmacology, Vol. 21, 185-220(1990).

Treatment of drug and multidrug resistance typically involves thecoadministration of a drug suitable for treatment of the disease and acompound known as a drug resistance modulator or a multidrug resistancemodulator. Drug and multidrug resistance modulators act through variousmechanisms to cause a drug or drugs suitable for treatment of a diseaseto begin and/or continue to function as a therapeutic agent.

One known mechanism by which certain drug and multidrug resistancemodulators function is by their interaction with a protein that isvariously called Multidrug-Resistance 1 protein (MDR1),Pleiotropic-glycoprotein (P-glycoprotein), Pgp or P170, referred toherein as “P-glycoprotein”. P-glycoprotein is endogenous in cellmembranes, including certain drug resistant cells, multidrug resistanttumor cells, gastrointestinal tract cells, and the endothelial cellsthat form the blood brain barrier. P-glycoprotein acts as an efflux pumpfor the cell. Certain substances, undesirably including treatment drugsfor various diseases, are pumped out of the cell by the P-glycoproteinprior to their having an effect on the cell. Drug and multidrugresistance modulators interact with P-glycoprotein. This interactioninterferes with the P-glycoprotein “drug efflux pump” action therebypermitting the treatment drug to enter and remain in the cell and haveits intended effect.

In addition to inhibiting the efflux of various drugs from tumor cells,drug and multidrug resistance modulators that interact withP-glycoprotein also function to enhance oral bioavailability ofnutrients or drugs, that are affected by the action of P-glycoprotein,through the gastrointestinal tract. Oral bioavailability refers to theability of a drug that is administered orally to be transported acrossthe gastrointestinal tract and enter into the bloodstream. A drug ormultidrug resistance modulator that interacts with P-glycoprotein shouldenhance the oral bioavailability of a drug or nutrient by interferingwith the efflux pump action of P-glycoprotein.

P-glycoprotein is believed to be present on both sides of theendothelial cell layer of the capillary tube of the brain. It is thiscapillary tube that functions physiologically as the blood-brainbarrier. The blood brain barrier is believed to restrict the entry ofmany different types of compounds, including drugs whose site of actionis within the brain, from entering the brain. Certain drug and multidrugresistance modulators that interact with P-glycoprotein also canfunction to enhance bioavailability of a drug to the brain byinteracting with P-glycoprotein and thus interfering with the drugefflux pump action of P-glycoprotein on the treatment drug. Thisinterference permits more of the treatment drug to cross the blood-brainbarrier into the brain and remain there.

Certain drug or multidrug resistance modulators that interact withP-glycoprotein are known. They include: verapamil (a calcium channelblocker that lowers blood pressure and has also been found effective invitro for treating drug-resistant malaria), certain steroids,trifluoroperazine (a central nervous system agent), vindoline, andreserpine (an α-2 blocker with central nervous system properties).

U.S. Pat. No. 5,112,817 to Fukazawa et al. discloses certain quinolinederivatives useful for the treatment of multidrug resistance in cancer.One of the initially promising active agents, MS-073, was found to beactive in in vitro testing. However, MS-073 was found to have poor oralbioavailability and to suffer from instability problems in solution.Other compounds in the series, such as the biphenylmethylcarbonylderivative MS-209, have been found to have better stability and oralbioavailability, but require the administration of higher doses to beeffective as a multidrug resistance modulator.

PCT Patent Application WO 94/24107 discloses10,11-cyclopropyldibenzosuberane derivatives which are described asbeing useful as multidrug resistance modulators.

There remains a need to discover compounds that will interact withP-glycoprotein so that they will act as drug and multidrug resistancemodulators to treat drug and multidrug resistance in various diseases.Additional compounds that interact with P-glycoprotein are also neededto act to enhance bioavailability of a drug or drugs to the brain and/orto act to enhance oral bioavailability of a drug or drugs.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (A):

where R¹ and R² are independently hydrogen or halo; A is —CH₂—CH₂—,—CH₂—CHR⁴—CH₂—, or —CH₂—CHR⁵—CHR⁶—CH₂—, where R⁴ is —H, —OH, or acyloxy;one of R⁵ and R⁶ is —H, —OH, or acyloxy and the other is —H; and R³ is apolyaryl; and pharmaceutically acceptable salts and solvates thereof.

The present invention also provides pharmaceutical compositionscomprising a compound or pharmaceutically acceptable salt or solvatethereof of Formula (A) in association with a pharmaceutically acceptablecarrier, diluent, or excipient.

The present invention further provides a method of treatment for a drugresistant disease comprising coadministering to a mammal in need thereofa resistance modulating amount of a compound or salt or solvate thereofof Formula (A) and an effective amount of a treatment drug for said drugresistant disease.

The present invention further provides a method of treatment for amultidrug resistant disease comprising coadministering to a mammal inneed thereof a multidrug resistance modulating amount of a compound orsalt or solvate thereof of Formula (A) and an effective amount of atreatment drug for said multidrug resistant disease.

The present invention further provides a method for enhancingbioavailability of a drug to the brain, comprising coadministering to amammal in need thereof a therapeutically effective amount of said drugand an amount of a compound or salt or solvate thereof of Formula (A)sufficient to allow said drug to cross the blood-brain barrier and enterthe brain.

The present invention further provides a method for enhancing oralbioavailability of a drug comprising administering to a mammal in needthereof a therapeutically effective amount of said drug and an amount ofa compound or salt or solvate thereof of Formula (A) sufficient to allowsaid drug to be transported across the gastrointestinal tract and enterthe bloodstream.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are set forth to illustrate and define themeaning and scope of the various terms used to describe the inventionherein.

The term “alkyl” refers to a fully saturated monovalent radical havingthe stated number of carbon atoms containing only carbon and hydrogen,and which may be a cyclic, polycyclic, branched or straight chainradical. This term is exemplified by radicals containing from 1-6 carbonatoms, such as, but not limited to, methyl, ethyl, propyl, t-butyl,pentyl, neopentyl, hexyl, and cyclohexyl. “Lower alkyl” refers to alkylradicals of from 1-4 carbon atoms.

The term “acyloxy” refers to the group —O—C(O)—R⁷ where R⁷ is C₁-C₆alkyl.

“Polyaryl” refers to monovalent fused ring systems that contain at leasttwo, and at most four fused aromatic rings. All the aromatic rings inthese systems may optionally be substituted, with the proviso that onlyone to three of the hydrogens on each ring may be replaced.

The term “aromatic” refers to rings containing one or more groups ofatoms in a cyclic array that contains clouds of delocalized π electronsabove and below the plane of the atoms; furthermore, the π clouds mustcontain a total of (4q+2) π electrons, where q is any positive integer.For purposes of this application “aromatic rings” are defined asunsaturated carbocyclic rings which can optionally be substituted.Aromatic rings can contain any number of carbon atoms, as long as theyretain their aromatic character and are sterically feasible. Thepreferred ring size is a six carbon ring.

The term “substituted” means one to three hydrogens on the structurehave been replaced with one to three moieties independently selectedfrom the group consisting of bromo, chloro, iodo, fluoro, C₁-C₆ alkyl,—COOH, amino, cyano, nitro, trifluoromethyl, difluoromethoxy, andhydroxyl groups, with the proviso that any substituted structure must beso configured that it is sterically feasible, affords a stable structureand is capable of reacting as described herein.

Examples of polyaryl ring systems used in the present invention include,but are not limited to, naphthyl, phenanthryl, anthryl, triphenylenyl,and chrysylenyl. Representative formulae for some of these polyaryl ringsystems include:

The term “carbocyclic” refers to a ring structure which has only carbonatoms in the ring.

The term “halo” refers to fluoro, bromo, chloro and iodo.

A “Pharmaceutically acceptable salt” may be any non-toxic salt derivedfrom an inorganic or organic acid that is suitable for administration asa drug. The salts are derived from inorganic acids, such as hydrochloricacid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfateas acetic salts), nitric acid, phosphoric acid and the like, and organicacids such as acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylicacid, p-toluene-sulfonic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, lactic acid, o-(4-hydroxy-benzoyl)benzoicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-naphthoic) acid, 3-phenylpropionic acid,trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid,glucuronic acid, glutamic acid, 3-hydroxy-2-naphthoic acid, stearicacid, muconic acid and the like.

A “pharmaceutically acceptable solvate” refers to a form of a compoundthat has clusters of solvent molecules clinging to the molecules of thecompound and which form is suitable for administration as a drug. Thesolvent may be water or any common organic solvent.

The term “bioavailability” refers to the degree and rate at which adrug, or other substance, becomes available to a target tissue within amammal.

The term “treatment” or “treating” means administering an appropriatetherapeutic or prophylactic amount of a compound to a mammal.

The term “effective amount” means a dosage sufficient to cause apositive change in the disease state being treated. The term “positivechange” will vary in meaning depending on the patient, the disease andthe treatment being undergone. For example, an effective amount of anoncolytic can be an amount that causes a reduction in the size of acancerous tumor, or where no reduction in tumor size occurs, aneffective amount of an oncolytic could be that amount that causes adecrease in analgesic consumption for the patient suffering from cancer.

The term “coadministering” means a disease treatment drug and a compoundof Formula (A), or a pharmaceutically acceptable salt or solvatethereof, are given to a mammal. The drug and the compound of Formula (A)or a pharmaceutically acceptable salt or solvate thereof, are given to amammal simultaneously or at different times.

The term “drug resistance” refers to the circumstance when a diseasedoes not respond to a treatment drug or drugs. Drug resistance can beeither intrinsic, which means the disease has never been responsive tothe drug or drugs, or it can be acquired, which means the disease ceasesresponding to a drug or drugs that the disease had previously respondedto.

“Multidrug resistance” means a specific type of drug resistancecharacterized by cross-resistance of a disease to more than onefunctionally and/or structurally unrelated drugs. Multidrug resistancecan be either intrinsic or acquired.

Compounds of the claimed invention are compounds of Formula (A):

where R¹ and R² are independently hydrogen or halo; A is —CH₂—CH₂—,—CH₂—CHR⁴—CH₂—, or —CH₂—CHR⁵—CHR⁶—CH₂—, where R⁴ is —H, —OH, or acyloxy;one of R⁵ and R⁶ is —H, —OH, or acyloxy and the other is —H; and R³ is apolyaryl; and pharmaceutically acceptable salts and solvates thereof.

The compounds of Formula (A) exist in two isomeric configurationsdefined by the relationship of the 10,11-cyclopropyl and the5-piperazinyl substituents on the dibenzosuberane. When the10,11-cyclopropyl and the 5-piperazinyl substituents are both orientedin the same direction vis-a-vis the dibenzosuberane (e.g., both up orboth down) the isomeric form is called “syn.” When the 10,11-cyclopropyland the 5-piperazinyl substituents are oriented in opposite directionsvis-a-vis the dibenzosuberane (e.g., one up and the other down) theisomeric form is called “anti.” In general, the drug/multidrugresistance activity of the compounds of Formula (A) in the “anti”configuration has been found to be far superior to the activity of thecompounds of Formula (A) in the “syn” configuration.

Certain compounds of Formula (A) will have an asymmetric center withinthe “A” substituent when R⁴ is not hydrogen or at whichever one of R⁵and R⁶ is not hydrogen. These compounds can exist in two stereochemicalforms, called (+) and (−) or called (R)- and (S)-, or as mixtures of thetwo sterioisomers. The (R)- and (S)- designation will be used in thisapplication.

While specific stereoisomers are disclosed and named, the presentinvention is to be interpreted to include both the “anti” and “syn”configurations, the individual (R)- and (S)- stereoisomers within thoseconfigurations, as well as mixtures, racemic and otherwise, thereof.

Preferred compounds of the claimed invention include:

(2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-syn-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-syn-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-syn-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-syn-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-syn-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

anti-1-{2-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]ethoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

anti-1-{2-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]ethoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

anti-1-{2-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]ethoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

anti-1-{2-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]ethoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

anti-1-{2-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]ethoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2R)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}phenanthrene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}anthracene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}triphenylene,or a pharmaceutically acceptable salt or solvate thereof,

(2S)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}chrysene,or a pharmaceutically acceptable salt or solvate thereof, and mixturesthereof.

A more preferred compound of the invention is (2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or pharmaceutically acceptable salts or solvates thereof. This morepreferred compound is illustrated in Formula (AI):

Generally, the compounds of Formula (A) are prepared by following theprocedures described in PCT Patent Application PCT/US94/04215 and U.S.Pat. No. 5,112,817, both incorporated herein by reference. The compoundsof Formula (A) are prepared by incorporating a10,11-cyclo-propyldibenzosuberone (optionally including non-hydrogensubstituents at the R¹ and R² positions) in place of thedibenzosuberone. The 10,11-cyclopropyldibenzosuberone can be prepared,for example, as described in “Imine Analogues of TricyclicAntidepressants,” by Ciganek, et al., J. Med. Chem., 1981, 24, 336-41;or in “Aminoalkyldibenzo[a,e]cyclopropa[c]-cycloheptene Derivatives. ASeries of Potent Antidepressants,” by Coyne and Cusic, J. Med. Chem.,1974, Vol. 17, No. 1, 72-75.

To make the compounds of Formula (A) the aryl alcohol used to make theR³ component of Formula (A) must be a polyaryl (two to four fusedaromatic carbocyclic ring) alcohol. The polyaryl alcohol is reacted asdescribed in PCT Patent Application PCT/US94/04215 (Page 13, lines35-44) and U.S. Pat. No. 5,112,817 (Column 15, lines 21-52) with acompound selected from a group that may include a nosyl (such as3-nitrophenyl-sulfonyl-glycidal) derivative as well as a tosyl or mesylderivative of 1-chloro-2,3-epoxybutane, 1-bromo-2,3-epoxy-butane,epibromohydrin or epichlorohydrin.

Isolation and purification of the compounds and intermediates can beeffected, if desired, by any suitable separation or purificationprocedure such as, for example, filtration, extraction, crystallization,column chromatography, thin-layer chromatography or thick-layerchromatography, or a combination of these procedures.

The compounds of Formula (A) can be converted to corresponding acidaddition salts. The conversion is accomplished by treatment with astoichiometric amount of an appropriate acid, which appropriate acidincludes inorganic acids, such as hydrochloric acid, hydrobromic acid,sulfuric acid (giving the sulfate and bisulfate as acetic salts), nitricacid, phosphoric acid and the like, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malicacid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, salicylic acid,p-toluene-sulfonic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, lactic acid, o-(4-hydroxy-benzoyl)benzoicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-naphthoic) acid, 3-phenylpropionic acid,trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid,glucuronic acid, glutamic acid, 3-hydroxy-2-naphthoic acid, stearicacid, muconic acid and the like. In the salt-forming step of thisinvention, the free base is typically dissolved in a polar organicsolvent, such as methanol or ethanol, and the acid is added in water,methanol or ethanol. The temperature is maintained at 0° C. to 50° C.The corresponding salt precipitates spontaneously or can be brought outof solution with a less polar solvent, or by evaporation of the solventor by cooling the solution.

In the step of liberating the free base of Formula (A) according to theinvention the acid addition salts of the compounds of Formula (A) can bedecomposed to the corresponding free bases by treatment with an excessof a suitable base, such as ammonia or sodium bicarbonate, typically inthe presence of an aqueous solvent, and at a temperature between 0° C.and 50° C. The free base is isolated by conventional means, such asextraction with an organic solvent. The stoichiometric excess must takeinto account the number of equivalents of acid bound by the base ofFormula (A).

As stated above, the present invention includes solvates of thecompounds of Formula (A) and the pharmaceutically acceptable saltstherein. A particular compound of the present invention or apharmaceutically acceptable salt thereof may form solvates with water orcommon organic solvents. Such solvates are included within the scope ofcompounds of the present invention.

Utility

The compounds of the present invention are useful as drug and multidrugresistance modulators. They are useful for treating drug and multidrugresistance after resistance becomes clinically evident, and can also beadministered at the time of initial drug therapy, before any clinicalresistance becomes evident, to enhance the activity of drugs from thebeginning of drug administration.

The compounds of the present invention are particularly useful for thetreatment of drug resistant and multidrug resistant cancer and drugresistant malaria.

The compounds of the present invention are also useful for enhancing theoral bioavailability of a drug.

The compounds of the present invention are also useful for enhancingbioavailability of a drug to the brain.

As stated above, the present invention includes mixtures of thecompounds or pharmaceutically acceptable salts or solvates of Formula(A). Preferred mixtures consist of racemic mixtures containing at leastone pair of enantiomers. A preferred mixture is a racemic mixture of the2R and 2S enantiomers ofanti-1-{3-[4-(10,11-difluorocyclopropyl-dibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}-naphthalene.

In Vitro Testing for Multidrug Resistance Modulation with CancerChemotherapeutic Drugs

Compounds are evaluated for their ability to show multidrug resistancemodulation when coadministered with an oncolytic. Cell cytotoxicityassays are conducted by growing a P-glycoprotein-expressing multidrugresistant cell line such as CEM/VLB₁₀₀ (available from, among others,Dr. William Beck of St. Jude's Research Hospital in Tennessee), P388 VCR(available through DCT Repository, NCI, Frederick, Md.) and CHCR5(available from, among others, Dr. Victor Ling, Vancouver, B.C. CancerAgency, Vancouver, B.C.) in the presence of an appropriate oncolytic andthe multidrug resistance modulator as described below.

MTT, {3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide],DOX (doxorubicin), VP-16 (etoposide) and VLB (vinblastine sulfate) canbe obtained from Sigma Chemical Co. (St. Louis, Mo.). Taxol® can beobtained from ICN Biomedicals, Inc. (Costa Mesa, Calif.). FBS (fetalbovine serum) can be purchased from Hyclone (Logan, Utah). L-glutamineand Minimum Essential Media for suspension cultures (SMEM) can bepurchased from GIBCO (Grand Island, N.Y.). Tissue culture Seroclusters96-well with round bottom wells can be obtained from Costar (Cambridge,Mass.). Tissue culture flask can be obtained from Corning Glass Works(Corning, N.Y.).

The human leukemia cell lines parental CCRF-CEM and the multidrugresistant CEM/VLB₁₀₀ (selected with 100 ng/ml vinblastine) can beprovided by William T. Beck (Beck, W. T., Mueller, M. J., and Tanzer L.R., Altered Surface Membrane Glycoproteins in Vinca Alkaloid—ResistantHuman Leukemic Lymphoblast, Cancer Research, 39, 2070-2076 (1979)). Thecells can be maintained in SMEM medium supplemented with 10% FBS and 2mM L-glutamine in a humidified incubator with 95% air and 5% CO₂. Cellnumber can be determined using a Coulter Counter model ZM. Cells can besubcultured every 3-4 days.

Cell viability can be determined using a modified MTT dye reductionmethod (Denziot, F., Lang, R., Rapid calorimetric assay for cell growthand survival modifications to the tetrazolium procedure giving improvedsensitivity and reliability, J. Immunological Methods, 89, 271-277,(1986)), as described:

Cells are harvested during the logarithmic growth phase, and seeded in96-well serocluster plates at 7.5×10³ cells/well and cultured for 72hours in the presence of serially diluted oncolytics (VLB, DOX, VP-16and Taxol®)±modulators. A single well assay is conducted using a fixedconcentration of VLB (4 ng/ml) and modulator (5 μM). The cytotoxicity ofthe modulator alone, at the same concentration is also determined.Modulators are prepared as 2 mM stocks in DMSO and added to the wells togive final concentrations ranging from 5 μM to 0.5 μM. After 72 hours,20 μl of freshly prepared MTT (5 mg/ml in Dulbecco's phosphate bufferedsaline pH 7.5) is added to each well and placed for 4 hours in a 37° C.incubator. Cells are pelleted at 1800 R.P.M. for 10 minutes in a SorvallRT6000B centrifuge. After centrifugation, 70 μl of medium is carefullyremoved from each well, and 100 μl of 2-propanol/0.04 N HCl is added todissolve the blue formazan stained cells. Cells are resuspended 5-10times with a multipipettor or until no particulate matter was visible.Plates are immediately read on a Yitertek MCC/340 microplate reader(Flow Laboratories (McLean, Va.) with a wavelength of 570 nm and areference wavelength of 630 nm). Controls are measured in quadruplicateand modulators in duplicate.

IC₅₀'s are calculated from semilog dose response curves in the presenceand absence of modulators for both the parent and resistant cell lines.The fold shift is calculated as the IC₅₀ for cells treated withoncolytic alone divided by the IC₅₀ for cells treated withoncolytic+modulator.

Taxol® was chosen as the test oncolytic for the studies reported hereindue to the high level of resistance of the cell line CEM/VLB₁₀₀ totaxol. The IC₅₀ of Taxol® is determined in the presence of varyingconcentrations of the modifier, with the goal of achieving full reversalactivity. Full reversal activity, or 100% reversal activity, is definedas the ability to achieve drug sensitivity in the multidrug resistantcell line which is equivalent to the sensitivity of the drug sensitiveparental cell line. This data is presented here as Rev₅₀ and Rev₁₀₀.These numbers are defined as the lowest concentration of modifier (inμM) which can achieve 50% and 100% reversal activity, respectively.

In Vitro Testing for Drug Resistance Modulation of Anti-Malarial Drugsused in the Treatment of Drug Resistant Malaria

Compounds are evaluated for their ability to exhibit drug resistancemodulation when coadministered with an anti-malarial drug used in thetreatment of drug resistant malaria. The tests are conducted by placingthe drug resistance modulator in the drug resistant malaria species inthe presence of an anti-malarial drug. The anti-malarial drug is a drugthat the drug resistant malaria species is known to be resistant to. Forexample, the malaria species P. lophurae and P. cynumolgi are bothresistant to the anti-malarial drug proguanil. Modulator activity isdefined as the ability to achieve drug sensitivity to the anti-malarialdrug in the drug resistant malaria species by coadministration of theanti-malarial drug and the drug resistance modulator of choice.

Further details on testing for reversal of drug resistance in variousmalaria species can be found in standard references about malaria, suchas: Chemotheraphy of Malaria, by Covell, et al., ©1955 by World HealthOrganization, Geneva, and Practical Malariology, 2nd Edition, by Russellet al., ©1963 by Oxford University Press.

Testing for Oral Bioavailability of a Compound

A simple test to determine oral bioavailability of a drug is toadminister the drug orally and then test for the presence of the drug,or its metabolites, in the blood using standard blood analyticaltechniques. The test is run twice, once with the drug administered byitself and the second time the drug is administered in the presence of adrug resistance modulator. The results are compared to see how much morecompound is orally bioavailable when the modulator is present.

Testing for Bioavailability of a Drug to the Brain by Testing forMovement of the Compound Across the Blood-Brain Barrier

An in vitro test for movement of a compound across the blood-brainbarrier is begun by growing a confluent monolayer of either bovine brainendothelial or mouse brain capillary endothelial cells on a porousfilter support to form a tight endothelium cell layer. The filtersupport is placed in a vessel containing phosphate buffered saline suchthat the only way for materials to get from one side of the vessel toanother is through the cell layer/porous filter support.

A known compound (e.g. mannitol) is placed in the vessel on the serosalside of the cell layer/porous filter. Samples are removed from thenon-serosal side of the cell layer/porous filter at 15-30 minuteintervals over a 3-6 hour time period. Standard analytical techniquesare used to determine the amount of known compound in the sample. Thisinformation is used to calculate the base line permeability of the celllayer/porous filter.

The drug of interest (e.g., oncolytic or anti-malarial) is then placedon one side of a vessel containing fresh saline and the same type ofcell layer/porous filter barrier. Samples are removed from the otherside at 15-30 minute intervals over a 3-6 hour time period. Standardanalytical techniques are used to determine the amount of drug ofinterest in those samples. The amount of drug of interest that migratesacross the barrier is indicative of the base line permeability of thecell layer/porous filter for that drug.

The test is then repeated, only this time the drug of interest and adrug resistance modulator are both placed on one side of a vesselprepared as before. Samples are pulled and tests are run as describedabove to see how much more of the drug of interest migrates across thecell layer/porous filter support with the drug resistance modulatorbeing present.

An in vivo test to determine whether a drug administered to a mammal hascrossed the blood brain barrier is to administer the drug to the mammalin any acceptable manner and then test for the presence of the drug, orits metabolites, in the mammal's cerebrospinal fluid.

The compounds of the present invention may be administered to anymammal. Of all mammals, it is believed that humans will benefit the mostfrom administration of these compounds.

The compounds of Formula (A) are administered at a therapeuticallyeffective dosage, e.g., a dosage sufficient for the compound to:

(i) act as a drug or multidrug resistance modulator when coadministeredwith a treatment drug for a drug or multidrug resistant disease;

(ii) enhance the oral bioavailability of a drug; and/or

(iii) enhance the bioavailability of a drug to the brain.

Treatment of a disease includes:

(i) preventing the disease, that is, causing the clinical symptoms ofthe disease not to develop;

(ii) inhibiting the disease, that is, arresting the development ofclinical symptoms; and/or

(iii) relieving the disease, that is, causing the regression of clinicalsymptoms.

The compounds of Formula (A) are typically co-administered eitherbefore, during or after the administration of a drug that treats thedisease in question. A preferred administration schedule is a continuousinfusion over the 24 hour period during which the treatment drug is alsoadministered. For cancer, a treatment drug would be a cancerchemotherapeutic agent, including, but not limited to, paclitaxel,doxorubicin, adriamycin, etoposide, teniposide, vinblastine,vincristine, mitomycin C, daunorubicin, and teniposide. For malaria atreatment drug would be an anti-malarial treatment drug, including butnot limited to, pamaquine, primaquine, mepacrine, doxycycline,chloroquine, amodiaquine, quinine, quinidine, pyrimethamine, proguanil,mefloquine and sulphadiazine.

A daily dose of drug or multidrug resistance modulator for all methodsof treatment described herein is from about 100 mg/M² of body surfacearea to about 1 g/M² of body surface area, preferably from about 200mg/M² to about 800 mg/M² of body surface area and most preferably fromabout 400 mg/M² to about 500 mg/M² of body surface area. The amount ofdrug or multidrug resistance modulator compound administered will, ofcourse, be dependent on the patient and the disease state being treated,the severity of the affliction, the manner and schedule ofadministration (e.g., oral administration one day prior to cancerchemotherapy as compared to intravenous administration during cancerchemotherapy) and the judgment of the prescribing physician.

The dosage level of the disease treatment drug is adjusted for eachrecipient to maximize the efficacy of the disease treatment drug whileminimizing any undesirable side effects. When a drug or multidrugresistance modulator is coadministered with a disease treatment drug,the dosage of the disease treatment drug may stay the same or bedecreased, depending upon the efficacy of the drug or multidrugresistance modulator in performing its function.

In employing the compounds of this invention for treatment of drug ormultidrug resistance, any pharmaceutically acceptable mode ofadministration can be used. The compounds of Formula (A) can beadministered either alone or in combination with other pharmaceuticallyacceptable excipients. These include solid, semi-solid and liquid dosageforms, such as, for example, tablets, capsules, powders, liquids,suspensions, suppositories or the like. The compounds of Formula (A) canalso be administered in sustained or controlled release dosage forms,including depot injections, osmotic pumps, pills, transdermal (includingelectrotransport) patches, and the like, for the prolongedadministration of the compound at a predetermined rate, preferably inunit dosage forms suitable for single administration of precise dosages.The compositions will typically include a conventional pharmaceuticalcarrier, diluent or excipient and a compound of Formula (A) or apharmaceutically acceptable salt thereof. In addition, thesecompositions may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc., such as the cancer chemotherapeutic agentslisted above.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable composition will contain from about 0.005%to about 95%, preferably from about 0.5% to about 50%, by weight of acompound or salt or solvate of Formula (A), the remainder being suitablepharmaceutical excipients, carriers and diluents.

One manner of administration for the conditions detailed above is oral,using a convenient daily dosage regimen which can be adjusted accordingto the degree of affliction. For such oral administration, apharmaceutically acceptable, non-toxic composition is formed by theincorporation of any of the normally employed excipients, such as, forexample, mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin,sucrose, magnesium carbonate, and the like. Such compositions includesolutions, suspensions, tablets, dispersible tablets, pills, capsules,powders, sustained release formulations and the like.

Preferably the oral compositions will take the form of a pill or tablet.Thus, the composition will contain along with the active ingredient: adiluent such as lactose, sucrose, dicalcium phosphate, or the like; alubricant such as magnesium stearate or the like; and a binder such asstarch, gum acacia, gelatin, polyvinylpyrrolidone, cellulose andderivatives thereof, and the like.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc., an active compound as definedabove and optional pharmaceutical adjuvants in a carrier, such as, forexample, water, saline, mannitol, aqueous dextrose, glycerol, glycol,ethanol and the like, to thereby form a solution or suspension. Ifdesired, the pharmaceutical composition to be administered may alsocontain minor amounts of non toxic auxiliary substances such as wettingagents, emulsifying agents, or solubilizing agents, pH buffering agentsand the like, for example, acetate, sodium citrate, cyclodextrinederivatives, sorbitan monolaurate, triethanolamine sodium acetate,triethanolamine oleate, etc. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 19th Edition, 1995.

Parenteral administration is generally characterized by injection (e.g.subcutaneously, intramuscularly, intravenously) or infusion through acentral line. Injectables can be prepared in conventional forms, eitheras liquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol, ethanol,mannitol or the like. In addition, if desired, the pharmaceuticalcompositions to be administered may also contain minor amounts ofnon-toxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents, solubility enhancers, and the like, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleate,cyclodextrins, etc. A preferred liquid solution for parenteraladministration contains an appropriate amount of compound in a 5%solution of mannitol in water.

A more recently devised approach for parenteral administration employsthe implantation of a slow-release or sustained-release system, suchthat a constant level of dosage is maintained. See, e.g., U.S. Pat. No.3,710,795.

The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject. However,percentages of active ingredient of from about 0.01% to about 10% insolution are employable, and will be higher if the composition is asolid which will be subsequently diluted to the above percentages.Preferably, the parenteral composition will contain from about 0.2% toabout 2% of the active agent in solution.

The preferred manner of administering the active compound is, at thepresent time, infusion through a central line.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Example 1

A) (S) 1-(1-Naphthyloxy)-2,3-epoxypropane

To a suspension of 48 mg (1.20 mmol) of sodium hydride (60% in mineraloil) in 3 mL of DMF were added 173 mg (1.20 mmol) of 1-naphthol whilestirring at 0° C. The reaction was allowed to warm to 25° C. and stirredan additional 1 hour. The reaction was recooled to 0° C., and a solutionof 260 mg (1.0 mmol) of (S)-(-)-(3-nitrophenylsulfonyl)-glycidol in 1 mLof DMF was added dropwise. The reaction was stirred at 0° C. for 2hours, poured into 25 mL of brine and the product extracted into ethylacetate (5X). The combined organic extracts were dried over sodiumsulfate and concentrated in vacuo to give 240 mg of the compound ofFormula (i) (S) 1-(1-Naphthyloxy)-2,3-epoxypropane, which was usedwithout further purification.

B)(2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}-naphthalene

A solution containing 50 mg (0.25 mmol) of4′—H—1′-(10,11-difluorocyclopropyldibenzosubarane)piperazine and 84 mg(0.26 mmol) of (S) 1-(1-Naphthyloxy)-2,3-epoxypropane (i) in 2 mL ofisopropanol was heated at reflux for 18 hours. The reaction was cooledto 25° C. and concentrated in vacuo. This crude material was purified byflash chromatography on a silica gel column using 2% methanol-methylenechloride as the eluent. The major fraction was collected andconcentrated in vacuo to give 150 mg of a white amorphous solid. A namefor the structure of Formula (AI) is(2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene.mp (free base)=84-90° C.

In vitro testing of this compound on the P-glycoprotein expressing cellline CEM/VLB₁₀₀ for multidrug resistance with the cancerchemotherapeutic drug Taxol® showed a Rev₁₀₀ (μM) of 1.0 and a Rev₅₀(μM) of 0.70.

The following formulation examples are illustrative only and are notintended to limit the scope of the invention in any way. “Activeingredient” means a compound of Formula (A) or a pharmaceuticallyacceptable salt or solvate thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active ingredient 250 Starch, dried 200 Magnesiumstearate  10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/capsule) Active ingredient 250 Cellulose, micro crystalline400 Silicon dioxide, fumed  10 Stearic acid  5 Total 665 mg

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 3

Tablets, each containing 60 mg of active ingredient, are made asfollows:

Quantity (mg/tablet) Active ingredient 60 Starch 45 Micro crystallinecellulose 35 Polyvinylpyrrolidone (as 10% solution in water) 4 Sodiumcarboxymethyl starch 4.5 Magnesium stearate 0.5 Talc 1 Total 150

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Formulation 4

Capsules, each containing 80 mg of active ingredient, are made asfollows:

Quantity (mg/capsule) Active ingredient 80 Starch 59 Micro crystallinecellulose 59 Magnesium stearate 2 Total 200

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 5

Suppositories, each containing 225 mg of active ingredient, are made asfollows:

Quantity (mg/unit) Active ingredient   225 Saturated fatty acid 2,000glycerides Total 2,225

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 6

Suspensions, each containing 50 mg of active ingredient per 5 mL dose,are made as follows:

Quantity Active ingredient(s) 50 mg Sodium carboxymethyl cellulose 50 mgSyrup 1.25 mL Benzoic acid solution 0.10 mL Flavor q.v. Color q.v.Purified water to total 5 mL

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An intravenous formulation may be prepared as follows:

Quantity Active ingredient   100 mg Isotonic saline 1,000 mL

What is claimed is:
 1. A method of treatment of drug resistant malariacomprising coadministering to a mammal in need thereof a resistancemodulating amount of a compound or salt or hydrate thereof of Formula A

where R¹ and R² are independently hydrogen or halo; A is —CH₂—CH₂,—CH₂—CHR⁴—CH₂—, or —CH₂—CHR⁵—CHR⁶—CH₂—, where R⁴ is —H, —OH, or acyloxy;one of R⁵ and R⁶ is —H, —OH or acyloxy, and the other is —H,; and R³ isa naphthalene; and an effective amount of an anti-malarial drug ordrugs, selected from the groups consisting of pamaquine, primaquine,mepacrine, doxycycline, chloroquine, amodiaquine, quinine, quinidine,pyrimethamine, proguanil, mefloquine, and sulphadiazine.
 2. The methodof claim 1 wherein the compound is selected from the group consisting of(2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2R)-syn-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2R)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2R)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2R)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2R)-anti-1-{2-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin1-yl]ethoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2R)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2S)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxybutoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2S)-anti-1-{4-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-3-hydroxybutoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2S)-anti-1-{3-[4-(10,11-cyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2S)-anti-1-{3-[4-(10,11-fluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof,(2S)-anti-2-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof.
 3. The methodof claim 1 wherein the compound is(2R)-anti-1-{3-[4-(10,11-difluorocyclopropyldibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}naphthalene,or a pharmaceutically acceptable salt or hydrate thereof.